tbuckley/cabot-search huggingface dataset:
Abstract PD14-02: PD14-02 Ten-year follow-up of an image-based AI risk model for breast cancer
Authors: Mikael Eriksson, Kamila Czene, Emily F. Conant, Per Hall
Journal: Cancer Research (2023)

Abstract Background: Artificial intelligence based, image-derived short-term risk models for breast cancer have shown high discriminatory performance compared to traditional lifestyle familial-based risk models. However, the long-term performance has not yet been investigated. Methds: In this study, we investigated the long-term performance for predicting breast cancer throughout 10 years using an image-based risk model and compared the results to a traditional lifestyle familial-based risk model. We performed a nested case-control study based on a mammography screening cohort conducted since 2010 in Sweden for women aged 40-74. Mammograms, age, lifestyle and familial risk factors were collected at study entry. In the breast cancer register update in 2022; 2,028 incident breast cancers were included together with 8,398 controls that were matched to the cases on year of prior baseline mammogram. The image-based model extracted mammographic features (density, microcalcifications, masses, left-right breast asymmetries of these features) and age from the baseline mammograms. Tyrer-Cuzick risk model used self-reported lifestyle and familial risk factors to estimate risk at study-entry. Absolute risks were estimated using the risk models. We estimated model performances using Area Under the receiver operating characteristic Curves (AUC) statistics of the absolute risks and, risk ratios of women classified as high-risk and low risk using NICE and USPSTF guidelines. Results: The AUCs of the image-derived risk model ranged from 0.76 (95%CI 0.72-0.81) to 0.66 (95%CI 0.65-0.67) for breast cancers developed 1-10 years after study-entry. The corresponding Tyrer-Cuzick AUCs were 0.68 (95%CI 0.63-0.73) to 0.62 (95%CI 0.60-0.63). For estrogen negative and symptomatic cancers, the AUCs for the image-derived model were ≥0.75 during the first 2 years. Women with high and low mammographic density showed similar AUCs. Throughout the 10-years of follow-up, 20% of all women with cancers were deemed high risk at study-entry by the image-derived risk model compared to 6% of all women with cancers identified as high risk by the lifestyle familial-based model (p&amp;lt; 0.01). Conclusion: The image-derived model outperformed the lifestyle familial-based model both for short-term and long-term risk assessment and, could be used for identifying women who possibly could benefit from additional examinations and primary prevention. Citation Format: Mikael Eriksson, Kamila Czene, Emily F. Conant, Per Hall. PD14-02 Ten-year follow-up of an image-based AI risk model for breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD14-02.
Abstract P4-08-16: Selective Androgen Receptor Modulators in combination with CDK4/6 inhibitors demonstrate anti-cancer activity in preclinical treatment resistant ER+AR+ breast cancer models
Authors: Allegra Freelander, Geraldine laven-Law, Leila Eshraghi, Nimmy Geetha, Peta Somerville, Marie Pickering, Sarah Alexandrou, C. Elizabeth Caldon, Wayne D. Tilley, Theresa E. Hickey, Elgene Lim
Journal: Cancer Research (2023)

Abstract Background: The Androgen Receptor (AR) is expressed in up to 90% of all ER+ breast cancers and has been associated with better patient outcome. While androgens were used at a high dose as an anticancer therapy historically, this was discontinued with the advent of Tamoxifen due to virilising effects. Non-steroidal, tissue selective AR modulators (SARMs) represent an attractive alternative, offering a targeted approach to AR activation. Recent compelling pre-clinical data has established that the AR is a tumour suppressor in ER+ breast cancers and that AR activation with a natural androgen or a SARM suppressed ER-driven tumour growth, in preclinical models of endocrine-sensitive and -resistant ER+ breast cancer. Here, we evaluate the efficacy of a SARM (enobosarm) and a natural AR ligand (dihydrotestosterone, DHT) in the context of metastatic, CDK4/6 inhibitor (CDK4/6i) resistant breast cancer. Methods: Enobosarm and palbociclib treatments were evaluated in vitro by colony forming assays using CDK4/6i resistant (MCF7 PalbR) and both endocrine and CDK4/6i resistant (MCF7 cTamPalbR) cell lines. Next, enobosarm or DHT and palbociclib treatment were evaluated in vivo using endocrine and CDK4/6i resistant ER+ patient derived xenograft models (PDX) and cell line xenograft models. IHC, RNA and ChIP sequencing (AR, ER, H3K27ac) were subsequently performed on the harvested tumours. Results: While in vitro and in vivo growth of CDK4/6i resistant preclinical models was inhibited by treatment with a SARM or DHT alone, growth inhibition was more potent and durable in combination with a CDK4/6i. Gene set enrichment analysis of RNA-seq data integrated with ChIP-seq data revealed upregulation of an AR gene signature associated with a better prognosis following treatment with SARM. Co-treatment with a SARM and a CDK4/6i also enhanced AR signalling compared to SARM alone indicating an interaction of the two signalling pathways. Conclusion: Our data indicates that combination treatment with an AR agonist and a CDK4/6i represents a novel therapeutic strategy for CDK4/6i resistant ER+AR+ breast cancers Citation Format: Allegra Freelander, Geraldine laven-Law, Leila Eshraghi, Nimmy Geetha, Peta Somerville, Marie Pickering, Sarah Alexandrou, C. Elizabeth Caldon, Wayne D. Tilley, Theresa E. Hickey, Elgene Lim. Selective Androgen Receptor Modulators in combination with CDK4/6 inhibitors demonstrate anti-cancer activity in preclinical treatment resistant ER+AR+ breast cancer models. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-16.
Abstract P6-01-28: Tangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers
Authors: Adel Alblihy, Ahmed Shoqafi
Journal: Cancer Research (2023)

Abstract The MRE11–RAD50–NBS1 (MRN) complex is critical for genomic stability. Although germline mutations in MRN may increase breast cancer susceptibility, such mutations are extremely rare. Here, we have conducted a comprehensive clinicopathological study of MRN in sporadic breast cancers. We have protein expression profiled for MRN and a panel of DNA repair factors involved in double-strand break repair (BRCA1, BRCA2, ATM, CHK2, ATR, Chk1, pChk1, RAD51, γH2AX, RPA1, RPA2, DNA-PKcs), RECQ DNA helicases (BLM, WRN, RECQ1, RECQL4, RECQ5), nucleotide excision repair (ERCC1) and base excision repair (SMUG1, APE1, FEN1, PARP1, XRCC1, Pol β) in 1650 clinical breast cancers. The prognostic significance of MRE11, RAD50 and NBS1 transcripts and their microRNA regulators (hsa-miR-494 and hsa-miR-99b) were evaluated in large clinical datasets. Expression of MRN components was analysed in The Cancer Genome Atlas breast cancer cohort. We show that low nuclear MRN is linked to aggressive histopathological phenotypes such as high tumour grade, high mitotic index, oestrogen receptor- and high-risk Nottingham Prognostic Index. In univariate analysis, low nuclear MRE11 and low nuclear RAD50 were associated with poor survival. In multivariate analysis, low nuclear RAD50 remained independently linked with adverse clinical outcomes. Low RAD50 transcripts were also linked with reduced survival. In contrast, overexpression of hsa-miR-494 and hsa-miR-99b microRNAs was associated with poor survival. We observed large-scale genome-wide alterations in MRN-deficient tumours contributing to aggressive behaviour. We conclude that MRN status may be a useful tool to stratify tumours for precision medicine strategies. Citation Format: Ahmed Shoqafi. Tangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-28.
Abstract P4-02-09: Evaluation of the Automated Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) Cartridge Assay for Predicting Early Disease Progression and Survival: TBCRC-005 Prospective Trial
Authors: Kala Visvanathan, Leslie Cope, Mary Jo Fackler, Michael Considine, Lisa Carey, Andres Forero-Torres, James N. Ingle, Nancy U. Lin, Rita Nanda, Anna Maria Storniolo, Suzana Tulac, Natalie C. Wu, Sudhakar Marla, Neesha R. Venkatesan, Antonio C. Wolff, Saraswati Sukumar
Journal: Cancer Research (2023)

Abstract Purpose: We previously demonstrated that high levels of circulating methylated DNA are associated with subsequent disease progression in women with metastatic breast cancer (MBC). In this study, we validated the clinical utility of a Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) prototype assay using the GeneXpert® cartridge system for early assessment of disease progression in MBC. Study Design: The 9-marker, LBx-BCM prototype assay was evaluated in TBCRC-005, a prospective biomarker study, using plasma collected at baseline, week 4 and week 8 from 144 MBC patients. Results: At week 4 MBC patients with high cumulative methylation (CM) had a significantly shorter median PFS (2.88 months v 6.60 months, p = 0.001) and OS (14.52 months v 22.44 months, p=0.005) compared to those with low CM. In a multivariable model, high versus low CM was also associated with shorter PFS (HR = 1.90, 95%CI 1.20-3.01; p =0.006). Change in CM from baseline to week 4 (OR = 4.60, 95%CI 1.77, 11.93; p = 0.002) and high levels of CM at week 4 (OR = 2.78, 95%CI 1.29, 5.99; p = 0.009) were associated with progressive disease at the time of first restaging. A robust risk model (AUC = 0.733) based on week 4 circulating CM levels was developed to predict disease progression as early as 3 months after initiating a new treatment. Conclusion: The easy to perform and automated LBx-BCM prototype assay is a promising clinical tool for detecting disease progression early after initiating treatment in women with MBC. Further validation in larger clinical datasets is needed. Citation Format: Kala Visvanathan, Leslie Cope, Mary Jo Fackler, Michael Considine, Lisa Carey, Andres Forero-Torres, James N. Ingle, Nancy U. Lin, Rita Nanda, Anna Maria Storniolo, Suzana Tulac, Natalie C. Wu, Sudhakar Marla, Neesha R. Venkatesan, Antonio C. Wolff, Saraswati Sukumar. Evaluation of the Automated Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) Cartridge Assay for Predicting Early Disease Progression and Survival: TBCRC-005 Prospective Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-09.
Abstract PD9-01: Stromal mediators of lymphocyte exclusion and dysfunction in triple negative breast cancer
Authors: Julia Chen, Sunny Wu, Travis Ruan, Iveta Slapetova, Ewan Millar, Elgene Lim, Alex Swarbrick
Journal: Cancer Research (2023)

Abstract Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with poor prognosis and limited treatment options. One of the mechanisms contributing to this is the ability of TNBC tumors to evade anti-tumour response, limiting the success of immune-checkpoint therapy. In recent studies of the tumor microenvironment, stromal cells have emerged as potential important mediators of lymphocyte function in TNBC. Multi-omics studies from our group and others have elucidated the heterogeneity of stromal cells and their interactions with immune cells in TNBC. However, the clinical relevance and functional characteristics of these relationships remain poorly explored. Our previous work revealed functionally distinct subpopulations of stromal cells in breast cancer: endothelial cells, myofibroblast-like cancer-associated fibroblasts (myCAFs), inflammatory-CAFs (iCAFs), and perivascular-like cells which resemble pericyte and smooth muscle cells in immature and differentiated states (imPVLs; dPVLs), respectively. Here we directly explored the clinical relevance of these stromal subpopulations and their association with immune evasion in a large independent TNBC cohort with long-term survival data. Using markers derived from our single-cell multi-omics studies, we performed multiplex immunofluorescence using the OPAL9 platform on tumor microarrays from 222 TNBC patients to mark myCAFs, iCAFs, dPVLs, endothelial cells, CD8 and/or PD1 positive T-cells. Digital imaging analysis (QuPath) revealed a significant negative correlation between the abundance of stromal cells and CD8 T cells. This cytotoxic T-cell exclusion is primarily driven by smooth muscle dPVLs. Parallel to this T-cell exclusion, our functional studies demonstrate that stromal cells suppress T-cell proliferation. Using multiple ex vivo co-culture models of primary TNBC CAFs and peripheral blood mononuclear cells (PBMCs) from healthy and matched donors, we show that CAFs suppress the proliferative capability of CD4 and CD8 T-cells. ScRNA-seq of these co-culture models demonstrate that CAF educated T cells are driven into a LAG3+ exhausted state enriched for canonical pathways of immunosuppressive cytokine signaling. Our findings suggest that manipulation of these stromal subpopulations could elicit a more effective immune response in a subset of patients through inhibiting T-cell dysfunction and exclusion. Citation Format: Julia Chen, Sunny Wu, Travis Ruan, Iveta Slapetova, Ewan Millar, Elgene Lim, Alex Swarbrick. Stromal mediators of lymphocyte exclusion and dysfunction in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD9-01.
Abstract P4-03-16: Association between tamoxifen and the incidence of cataract in ductal carcinoma in situ patients
Authors: Dooreh Kim, Woo-Chan Park, Soyoung Jeon, Hye Sun Lee, Chang Ik Yoon
Journal: Cancer Research (2023)

Abstract Background Tamoxifen is used to improve oncologic outcomes in a hormone receptor-positive breast cancer. High-dose tamoxifen induced ocular toxicities, and regular dose of tamoxifen is known to increase the risk of cataracts in landmark studies. The current study’s objective is to review the incidence of cataracts in ductal carcinoma in situ (DCIS) patients who received adjuvant tamoxifen treatment, which can exclude the effect of other treatment modalities such as chemotherapy and target therapy. Method Data were obtained from the National Health Insurance claims database of the Health Insurance Review and Assessment Service in South Korea. Patients diagnosed with DCIS were sorted and retrospectively reviewed for the incidence of cataracts. The primary study outcome was the incidence of cataracts according to tamoxifen, and the incidence of cataracts was defined by concomitant diagnostic and behavioral code based on International Code of Disease, 10th revision. Results A total of 12,032 patients diagnosed with DCIS and received breast surgery from 2009 to 2015 were cut down to 4,759 patients, excluding those who already had cataracts, malignancies, or had developed cataracts within a year of breast cancer surgery. There were 3,037 patients who received tamoxifen and 1,722 patients who did not, median age of 49 years old. The incidence of cataracts was similar according to the use of tamoxifen, 7.6% and 7.7% respectively. The risk of developing cataracts did not increase with or without tamoxifen, even in the group who received adjuvant tamoxifen for more than two years (HR 0.978, 95% CI 0.782-1.222, p=0.843). The findings were consistent after propensity score matching (HR 1.072, 95% CI 0.829-1.388, p=0.595). Conclusions In a nationwide cohort study, the risk of cataracts in DCIS patients is similar whether the tamoxifen is used or not. Citation Format: Dooreh Kim, Woo-Chan Park, Soyoung Jeon, Hye Sun Lee, Chang Ik Yoon. Association between tamoxifen and the incidence of cataract in ductal carcinoma in situ patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-16.
Abstract PL2: Plenary Lecture 2: Premenopausal ER+ Breast Cancer: Past, Present, and Future
Authors: Carlos Arteaga, Prudence Francis
Journal: Cancer Research (2023)

Abstract Adjuvant endocrine therapy for premenopausal ER+breast cancer had a relatively challenging initial pathway. The earliest trials testing adjuvant ovarian ablation in premenopausal breast cancer were hampered by the lack of ability to test for the relevant target, namely the estrogen receptor (ER). Therefore, trials testing adjuvant ovarian ablation and subsequently ovarian suppression with gonadotropin releasing hormone agonists (GnRHa) were diluted by the inclusion of women with estrogen receptor negative tumors. The subsequent demonstration of the effectiveness of adjuvant chemotherapy, initially with the CMF regimen, diverted some attention away from adjuvant endocrine therapy in premenopausal women, notwithstanding the fact that CMF, initially given for 12 months, resulted in permanent ovarian function suppression in many premenopausal women. Use of adjuvant CMF made it even more challenging to discern the added value of ovarian ablation or suppression. Oral adjuvant endocrine therapy with the selective estrogen receptor modulator tamoxifen became recommended for postmenopausal women, subsequently refined to only those with ER+ breast cancer, but the value of tamoxifen in premenopausal women was initially considered uncertain. Eventually, 5 years of adjuvant tamoxifen became a standard recommendation for premenopausal ER+ early breast cancer, although it took some time for evidence to emerge on the value of adding tamoxifen in women who received chemotherapy. The value of extending adjuvant endocrine therapy beyond 5 years was subsequently studied. More recent randomized premenopausal adjuvant endocrine therapy trials have focused of delineating the value of ovarian function suppression (OFS) added to tamoxifen or to an aromatase inhibitor. There are now a range of options for adjuvant endocrine therapy for premenopausal ER+ breast cancer, and identifying the clinical-pathologic features most appropriate for intensification of adjuvant endocrine therapy can assist with optimizing recommendations for an individual patient. Citation Format: Carlos Arteaga, Prudence Francis. Plenary Lecture 2: Premenopausal ER+ Breast Cancer: Past, Present, and Future [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PL2.
Abstract P2-26-13: Gene deletion of insulin receptor in MCF-7L breast cancer cells by CRISPR gene editing
Authors: Xihong Zhang, Marvis Monteiro, Douglas Yee
Journal: Cancer Research (2023)

Abstract The type I insulin-like Growth Factor Receptor (IGF-IR) plays important roles in breast cancer cell proliferation and metastasis. However, preclinical and clinical research targeting IGF-IR also revealed the potential for insulin receptor (IR) to compensate for IGF-1R inhibition. IR is expressed as two isoforms (IRA and IRB) through alternative splicing. The IRB is expressed in adult tissues and thought responsible for cell metabolism while IRA is expressed in fetal development to enhance cell growth. Since breast cancer cells usually express both IGF-IR and IRA/IRB, differential signaling by IRA and IRB has not been clearly demonstrated. To further define the role for IR, we used CRISPR technology for gene editing in exon 2 of IR in MCF-7L cells to delete IR. Cells were selected for absent IR expression by flow cytometry and Sanger sequencing confirmed that one of the clones (CL35) had the targeted 4 base pair deletions in exon 2. Immunoblotting using an antibody to the  subunit of IR showed no expression in CL35. Unexpectedly, 10 nM insulin exposure resulted in downstream AKT and Erk1,2 phosphorylation. Immunoprecipitation showed that IGF-IR was activated by the insulin in CL35 cells. Insulin signaling in CL35 through IGF-IR was inhibited by huEM164, an anti IGF-IR monoclonal antibody. Compared to MCF-7L parental cells, CL35 was more sensitive to IGF-I and less sensitive to insulin as demonstrated by downstream AKT phosphorylation and MTT monolayer growth assay. Insulin stimulated monolayer growth of CL35 measured by MTT was not affected in testing serum free media (SFM) unless transferrin was deleted from the media. These data suggest IGF-IR can function to activate signaling in response to insulin. To ensure that our clone does not contain alternate splicing products resulting in aberrant IR proteins, we are further sequencing IR mRNA in CL35. In conclusion, we have established an IR null breast cancer cell line with reduced sensitivity to insulin and increased sensitivity to IGF-I. This cell line can be used to express the IRA and IRB isoforms to characterize their function in breast cancer cells. Citation Format: Xihong Zhang, Marvis Monteiro, Douglas Yee. Gene deletion of insulin receptor in MCF-7L breast cancer cells by CRISPR gene editing [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-13.